Journal of Clinical Oncology, 2004 ASCO Annual Meeting Proceedings (Post-Meeting Edition).
Vol 22, No 14S (July 15 Supplement), 2004: 2021
© 2004 American Society of Clinical Oncology

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Abstract

A dose-escalation study of the quinoxaline antitumor agent R(+)XK469 (XK) in patients with refractory solid tumors

University of Chicago, Chicago, IL

2021

Background: XK is a member of the quinoxaline family of antitumor agents. COMPARE analysis of cytotoxicity data from the NCI-60 cell line screen showed that its mechanism of action is not comparable to that of any marketed cytotoxic agent. In vitro studies suggest that the antitumor activity of XK may be due to inhibition of topoisomerase IIß, induction of G₂-M cell cycle arrest by p53-dependent and mitogen-activated protein (MAP) kinase pathways, and/or pro-apoptotic interactions with the peripheral benzodiazepine receptor. Methods: XK was administered as a 30-minute intravenous infusion for 5 days at 15, 30, 60, 120, and 240 mg/d and every other day for 3 doses at 360, 540, 675, 850, 1100, and 1400 mg/d, repeated every 21 days. The dosing schedule was changed when pharmacokinetic (PK) analysis revealed a long half-life. Results: To date 42 pts (21 male/21 female, median age 60, median Karnofsky performance status 90%) have been treated at 11 dose levels. The principle site of toxicity has been bone marrow. Grade 3 anemia and thrombocytopenia have been observed at 1100 and 1400 mg. Grade 4 neutropenia on the scheduled day 1 of cycle 2 and fever in the setting of grade 4 neutropenia have been the only dose-limiting toxicities (DLT). Non-hematologic toxicities include grade 1–2 alopecia, anorexia, diarrhea, fever, headache, nausea, peripheral neuropathy, rash, stomatitis, and vomiting and grade 3 fatigue. Plasma concentrations of XK decline in a biphasic manner with a long mean terminal phase half-life of 60 h (CV 63%). Steady-state volume of distribution is 13 L (CV 23%); and mean total body clearance (CL) is 0.20 L/h (CV 50%), which is not correlated with dose (p=0.69) or BSA (p=0.93). All pts who experienced DLT had CL < 1 standard deviation (SD) below the mean. Conclusions: XK can be safely administered on a d 1, 3, 5 schedule without BSA-based dosing. As AUC increases with dose and 15% of our pts had CL 1 SD below the mean, safety concerns preclude further dose escalation > 1100 mg/d on this schedule. Cohort expansion continues at the phase II recommended dose of 1100 mg/d. Pharmacogenomic studies are ongoing to investigate the basis for the large PK variability.

Author Disclosure

Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Bristol-Myers Squibb

Abstract presentation from the 2004 ASCO Annual Meeting